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Background: We sought to investigate disparities in the utilization of next-generation genetic sequencing (NGS) across demographic groups related to several  common cancer subtypes., Methods: Data on patients aged 65 years or older with a diagnosis of gastrointestinal, lung, and breast cancer between 2015 and 2020 were obtained from the Medicare Standard Analytic Files. Propensity score matching was employed to reduce selection bias, and logistic regression analysis was performed to investigate racial, ethnic, and sex-based disparities in NGS utilization., Results: Among 1,466,105 individuals, only 1.8% (n = 26,608) underwent NGS. Median patient age was 76 years (IQR 71-82), 36.8% (n = 539,201) of patients were male, and 87.8% (n = 1,287,805) were non-Hispanic White. Of note, minority patients, including non-Hispanic Black individuals (no NGS: 7.2% vs. NGS: 5.2%) and Hispanics (no NGS: 0.9% vs. NGS: 0.5%), as well as individuals residing in socially vulnerable neighborhoods (no NGS: 32.6% vs. NGS: 30.7%) were less likely to undergo NGS testing (all p < 0.001). On multivariable analysis, non-Hispanic Black race/ethnicity (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.69-0.78), Hispanic race/ethnicity (OR 0.64, 95% CI 0.53-0.77), and males (OR 0.97, 95% CI 0.94-0.99) remained at lower odds of undergoing NGS., Conclusion: Non-Hispanic Black and Hispanic patients, along with socioeconomically vulnerable individuals, were less likely to undergo NGS. Addressing these inequities is crucial to ensure that all patients have equal opportunities to receive effective, personalized cancer care that is equitable across diverse populations., Competing Interests: Disclosure: Muhammad Muntazir Mehdi Khan, Mujtaba Khalil, Hunter Stecko, and Timothy M. Pawlik declare no conflicts of interest that may be relevant to the contents of this article., (© 2024. Society of Surgical Oncology.)

Rare diseases affect 6%-8% of the population and present diagnostic challenges, particularly for historically marginalized ethnic and racial groups. The Undiagnosed Diseases Network (UDN) aims to enhance diagnosis rates and research participation among such minoritized groups. A retrospective review was conducted from 2015 to 2023, analyzing 2235 UDN participants to evaluate its progress toward this objective. Data on demographics, disease phenotypes, diagnostic outcomes, and socioeconomic factors were collected and statistical analyses assessed differences among ethnic and racial groups. This demonstrated that Hispanic and Black non-Hispanic groups were underrepresented, while White non-Hispanic participants were overrepresented in the UDN compared to the US population. Individuals whose primary language was not English were also significantly underrepresented. Diagnosis rates varied, with the highest rates among Asian non-Hispanic (39.5%) and Hispanic (35.3%) groups and the lowest rate in the White non-Hispanic group (26.8%) (p < 0.001). Binomial logistic regression found, however, that only participant age and disease phenotype predicted the likelihood of receiving a diagnosis (p < 0.001). Persistent ethnic and racial disparities in UDN participation appear to be associated with major differences in application rates. Under-enrollment of historically marginalized ethnic and racial groups may be due to economic hardships and language barriers. No differences in the diagnostic yield among ethnic and racial groups were observed after controlling for other factors. This work highlights the value of comprehensive genetic evaluations for addressing healthcare disparities and suggests priorities for advancing inclusion in rare disease research., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Black patients with colon cancer (CC) exhibit more aggressive tumor biology and higher treatment resistance than white patients, even after adjusting for clinical and demographic factors. We investigated stage-specific transcriptional differences in tumor profiles of Black and white patients with CC., Patients and Methods: Patients with CC from The Cancer Genome Atlas Colon Adenocarcinoma database were categorized by disease stage and propensity-score matched between Black and white patients. Differential gene expression and pathway enrichment analyses were performed for each stage. Logistic regression and quadratic discriminant analysis (QDA) models were developed using consistently differentially expressed genes., Results: Of 247 patients, 128 had localized (22% Black), 81 had regional (74% Black), and 38 had distant disease (29% Black). Differential expression analysis revealed differences in 312 genes for localized, 105 for regional, and 199 for distant stages between Black and white patients. Pathway enrichment analysis showed downregulation of the IL-17 pathway in Black patients with localized disease. In total, five genes exhibited race-specific transcriptional differences across all stages: RAMACL, POLR2J3, POLR2J2, MUC16, and PRSS21. Logistic regression and QDA model performance indicated that these genes represent racial differences [area under the receiver operating characteristic curve (AUC): 0.863 and 0.880]., Conclusions: Significant transcriptional differences exist in CC between Black and white patients changing dynamically across disease stages, and involving genes with broad functions. Key findings include IL-17 pathway downregulation in Black patients with localized disease and a five-gene signature consistent across all stages. These findings may explain aspects of racial disparities in CC, emphasizing the need for race-specific research and treatment strategies., Competing Interests: Disclosure: The authors have no relevant conflicts of interests, financial or otherwise, to disclose. No specific source of funding was received for this study. This study was deemed exempt from institutional review board approval owing to the publicly available and deidentified nature of the dataset., (© 2024. The Author(s).)

Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r 2  < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10 -5 ), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability., (© 2024 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.)

Purpose: Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancers. BTCs have a number of genomic alterations, including isocitrate dehydrogenase 1 ( IDH1 ) mutations, fibroblast growth factor receptor 2 ( FGFR2 ) rearrangements, and ERBB2 amplifications. Therapies targeting these alterations have shown clinical benefit in patients with BTCs in the United States. However, molecular differences between races in BTCs are largely unknown. In particular, the genomic profiles of African American (AA) patients with BTCs have been infrequently reported. We sought to identify key genomic differences between AA and Caucasian patients with BTCs in the United States in the Foundation Medicine and American Association for Cancer Research (AACR) GENIE databases., Methods: BTC patients from AA and Caucasian patients from the Foundation Medicine and AACR GENIE databases were retrospectively reviewed. BTCs were divided into ICC, ECC, and GBCs in the Foundation Medicine database. BTCs were divided into cholangiocarcinomas and GBCs in the AACR GENIE database., Results: The mean age of AA patients with BTCs was lower compared with Caucasians. TP53 and FGFR2 alterations were significantly more frequent in AA patients compared with Caucasian patients with BTCs. IDH1 mutations in Caucasian patients with BTCs were double that of AA patients., Conclusion: The results of this study suggest that significant genomic differences exist between races and warrant further investigation.

This study aimed to examine whether a reported SSc-associated SNP rs2841277 in the PLD4 gene identified in an Asian population was also associated with SSc in European American (EA). The EA cohort consisting of 1005 SSc patients and 961 healthy controls was examined in this study. TaqMan genotyping assays were performed to examine the SNP. Exact P-values were obtained from 2 × 2 tables of allele counts and disease status. In contrast to the previous reports in a Japanese population, SSc patients of EA did not show an association of PLD4 rs2841277 with SSc in general (P = 0.231, OR = 0.89, 95% CI = 0.73-1.08), or with clinical subtypes of dcSSc (P = 0.302, OR = 0.86, 95% CI = 0.65-1.13) and lcSSc (P = 0.369, OR = 0.90, 95% CI = 0.72-1.12), or with autoantibody subtypes including ATA (P = 0.126, OR = 0.74, 95% CI = 0.51-1.08), ACA (P = 0.943, OR = 1.01, 95% CI = 0.77-1.34), ARP3 (P = 0.155, OR = 0.77, 95% CI = 0.53-1.1), or Anti-RNP (P = 0.660, OR = 0.73, 95% CI = 0.29-1.84). We found a lack of association of the PLD4 SNP rs2841277 with SSc in an EA population. This is the first study to report a discrepancy in the genetic association between the PLD4 SNP and SSc. This may be explained by genetic heterogeneity between Japanese and EA populations, with genetic ancestry contributing to this variation. Further verification in diverse ancestral populations is warranted., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Androgen receptor (AR)-negative triple-negative breast cancer (TNBC), often termed quadruple-negative breast cancer (QNBC), disproportionately impacts women of African descent, leading to poorer overall survival (OS). MiRNAs regulate the expression of gene drivers involved in critical signaling pathways in TNBC, such as the AR gene, and their expression varies across races and breast cancer subtypes. This study investigates whether differentially expressed miRNAs influence AR transcription, potentially contributing to the observed disparities between African American (AA) and European American (EA) QNBC patients. Race-annotated TNBC samples (n = 129) were analyzed for AR expression status and revealed the prevalence of QNBC in AA patients compared to EA (76.6% vs. 57.7%) and a significant association of AR loss with poor survival among AAs. The Cancer Genome Atlas (TCGA) RNA-seq data showed that AAs with TNBC (n = 32) had lower AR mRNA levels than EAs (n = 67). Among TCGA patients in the AR-low group, AAs had significantly poorer OS than EAs. In our cohort, 46 miRNAs exhibited differential expression between AAs and EAs with QNBC. Ten of these miRNAs (miR-1185-5p, miR-1305, miR-3161, miR-3690, miR-494-3p, miR-509-3-5p, miR-619-3p, miR-628-3p, miR-873-5p, and miR-877-5p) were predicted to target the AR gene/signaling. The loss of AR expression is linked to poorer prognoses in AA women. The understanding of the specific miRNAs involved and their regulatory mechanisms on AR expression could provide valuable insights into why AA women are more prone to QNBC.

Purpose: In genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous GWAS identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore¸ our goal was to investigate ChrX variants for association with AMD., Methods: We genotyped 29 629 non-Hispanic White (NHW) individuals (M/F:10404/18865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1 221 623 variants on ChrX. Age, informative PCs, and subphenotypes were covariates for logistic association analyses with Fisher's correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath., Results: Logistic association on NHW individuals with sex correction identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P < 1 × 10-6,Fisher's combined-corrected). Association testing of the subphenotypes of choroidal neovascularization and geographic atrophy (GA), identified variants in DMD associated with GA (P < 1 × 10-6, Fisher's combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P < 0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9. Pathway analysis using GSEASNP and DAVID identified genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P < 0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs showed association with brain disorders and fatty acid elongation (P < 0.05). A long noncoding RNA on ChrX near the DMD locus was also associated with AMD (P = 4 × 10-7). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P = 2 × 10^-5)., Conclusions: Analysis of ChrX variation identifies several potential new locifor AMD risk and these variants nominate novel AMD pathways. Further analysis is needed to refine these results and to understand their biological significance and relationship with AMD development in worldwide populations., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Early mid-life is marked by accumulating risks for cardiometabolic illness linked to health-risk behaviors like nicotine use. Identifying polygenic indices (PGI) has enriched scientific understanding of the cumulative genetic contributions to behavioral and cardiometabolic health, though few studies have assessed these associations alongside socioeconomic (SES) and lifestyle factors., Aims and Methods: Drawing on data from 2337 individuals from the United States participating in the National Longitudinal Study of Adolescent to Adult Health, the current study assesses the fraction of variance in five related outcomes-use of conventional and electronic cigarettes, body mass index (BMI), waist circumference, and glycosylated hemoglobin (A1c)-explained by PGI, SES, and lifestyle., Results: Regression models on African ancestry (AA) and European ancestry (EA) subsamples reveal that the fraction of variance explained by PGI ranges across outcomes. While adjusting for sex and age, PGI explained 3.5%, 2.2%, and 0% in the AA subsample of variability in BMI, waist circumference, and A1c, respectively (in the EA subsample these figures were 7.7%, 9.4%, and 1.3%). The proportion of variance explained by PGI in nicotine-use outcomes is also variable. Results further indicate that PGI and SES are generally complementary, accounting for more variance in the outcomes when modeled together versus separately., Conclusions: PGI are gaining attention in population health surveillance, but polygenic variability might not align clearly with health differences in populations or surpass SES as a fundamental cause of health disparities. We discuss future steps in integrating PGI and SES to refine population health prediction rules., Implications: Study findings point to the complementary relationship of PGI and socioeconomic indicators in explaining population variance in nicotine outcomes and cardiometabolic wellness. Population health surveillance and prediction rules would benefit from the combination of information from both polygenic and socioeconomic risks. Additionally, the risk for electronic cigarette use among users of conventional cigarettes may have a genetic component tied to the cumulative genetic propensity for heavy smoking. Further research on PGI for vaping is needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Homo sapiens and Neanderthals underwent hybridization during the Middle/Upper Paleolithic age, culminating in retention of small amounts of Neanderthal-derived DNA in the modern human genome. In the current study, we address the potential roles Neanderthal single nucleotide polymorphisms (SNP) may be playing in autism susceptibility in samples of black non-Hispanic, white Hispanic, and white non-Hispanic people using data from the Simons Foundation Powering Autism Research (SPARK), Genotype-Tissue Expression (GTEx), and 1000 Genomes (1000G) databases. We have discovered that rare variants are significantly enriched in autistic probands compared to race-matched controls. In addition, we have identified 25 rare and common SNPs that are significantly enriched in autism on different ethnic backgrounds, some of which show significant clinical associations. We have also identified other SNPs that share more specific genotype-phenotype correlations but which are not necessarily enriched in autism and yet may nevertheless play roles in comorbid phenotype expression (e.g., intellectual disability, epilepsy, and language regression). These results strongly suggest Neanderthal-derived DNA is playing a significant role in autism susceptibility across major populations in the United States., (© 2024. The Author(s).)

Overall, gastric adenocarcinoma (GC) incidence rates have declined in recent years, but racial and ethnic disparities persist. Individuals who identify as Hispanic/Spanish/Latino are diagnosed with GC at younger ages and have poorer outcomes than non-Hispanic individuals. However, our understanding of GC biology across racial/ethnic groups remains limited. We assessed tumor genomic patterns by race/ethnicity among 1019 patients with primary GC in the American Association for Cancer Research (AACR) Project GENIE Consortium. Hispanic individuals presented with significantly higher rates of ERBB2/HER2 amplification vs other racial/ethnic groups (Hispanic: 13.9% vs 9.8% non-Hispanic White, 8.1% non-Hispanic Asian, and 11.0% non-Hispanic Black; P < .001, FDR adjusted q < 0.001). Hispanic patients also had higher odds of an ERBB2 amplification vs non-Hispanic Whites in adjusted models (OR = 2.52, 95%CI = 1.20 to 5.33, P = .015). These findings underscore the important role of genomic factors in GC disparities. Ensuring equitable access to genomic profiling and targeted therapies, such as trastuzumab for HER2-overexpressing GC, is a promising avenue to mitigate GC disparities and improve outcomes., (© The Author(s) 2024. Published by Oxford University Press.)

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction., (© 2024. The Author(s).)

Interpersonal bias based on weight and race is widespread in the clinical setting; it is crucial to investigate how emerging genomics technologies will interact with and influence such biases in the future. The current study uses a virtual reality (VR) simulation to investigate the influence of apparent patient race and provision of genomic information on medical students' implicit and explicit bias toward a virtual patient with obesity. Eighty-four third- and fourth-year medical students (64% female, 42% White) were randomized to interact with a simulated virtual patient who appeared as Black versus White, and to receive genomic risk information for the patient versus a control report. We assessed biased behavior during the simulated encounter and self-reported attitudes toward the virtual patient. Medical student participants tended to express more negative attitudes toward the White virtual patient than the Black virtual patient (both of whom had obesity) when genomic information was absent from the encounter. When genomic risk information was provided, this more often mitigated bias for the White virtual patient, whereas negative attitudes and bias against the Black virtual patient either remained consistent or increased. These patterns underscore the complexity of intersectional identities in clinical settings. Provision of genomic risk information was enough of a contextual shift to alter attitudes and behavior. This research leverages VR simulation to provide an early look at how emerging genomic technologies may differentially influence bias and stereotyping in clinical encounters.

Background: Multiple novel protein biomarkers have been shown to be associated with prostate cancer risk using genetic instruments. This study aimed to externally validate the associations of 30 genetically predicted candidate proteins with prostate cancer risk using aptamer-based levels in US Black and White men in the Atherosclerosis Risk in Communities (ARIC) study. Plasma protein levels were previously measured by SomaScan® using the blood collected in 1990-1992., Methods: Among 4864 eligible participants, we ascertained 667 first primary prostate cancer cases through 2015. Hazard ratios (HRs) of prostate cancer and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for tertiles of each protein. We adjusted for age, race, and other risk factors., Results: Of the 30 proteins and considering a nominal p trend < 0.05, two were positively associated with prostate cancer risk-RF1ML (tertile 3 vs. 1: HR = 1.23; 95% CI 1.02-1.48; p trend = 0.037) and TPST1 (1.28, 95% CI 1.06-1.55; p trend = 0.0087); two were inversely associated-ATF6A (HR = 0.80, 95% CI 0.65-0.98; p trend = 0.028) and SPINT2 (HR = 0.74, 95% CI 0.61-0.90; p trend = 0.0025). One protein, KDEL2, which was nonlinearly associated (test-for-linearity: p < 0.01) showed a statistically significant lower risk in the second tertile (HR = 0.79, 95% CI 0.65-0.95). Of these five, four proteins-ATF6A, KDEL2, RF1ML, and TPST1-were consistent in the direction of association with the discovery studies., Conclusion: This study validated some pre-diagnostic protein biomarkers of the risk of prostate cancer., (© 2024 Wiley Periodicals LLC.)

Background: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling., Methods: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study., Results: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci., Discussion: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants., Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Significance: Non-Hispanic Black patients diagnosed with prostate cancer between 2014 and 2019 and treated at a comprehensive cancer center were less likely to use tumor-specific genomic testing compared with non-Hispanic White patients. Disparities in the use of precision oncology technologies should be monitored and addressed to ensure equitable cancer care., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Breast cancer (BrCa) is the most common cancer for women globally. BrCa incidence varies by age and differs between racial groups, with Black women having an earlier age of onset and higher mortality compared to White women. The underlying biological mechanisms of this disparity remain uncertain. Here, we address this knowledge gap by examining the association between overall epigenetic age acceleration and BrCa initiation as well as the mediating role of race., Results: We measured whole-genome methylation (866,238 CpGs) using the Illumina EPIC array in blood DNA extracted from 209 women recruited from University Hospitals Cleveland Medical Center. Overall and intrinsic epigenetic age acceleration was calculated-accounting for the estimated white blood cell distribution-using the second-generation biological clock GrimAge. After quality control, 149 BrCa patients and 42 disease-free controls remained. The overall chronological mean age at BrCa diagnosis was 57.4 ± 11.4 years and nearly one-third of BrCa cases were self-reported Black women (29.5%). When comparing BrCa cases to disease-free controls, GrimAge acceleration was 2.48 years greater (p-value = 0.0056), while intrinsic epigenetic age acceleration was 1.72 years higher (p-value = 0.026) for cases compared to controls. After adjusting for known BrCa risk factors, we observed BrCa risk increased by 14% [odds ratio (OR) = 1.14; 95% CI: 1.05, 1.25] for a one-year increase in GrimAge acceleration. The stratified analysis by self-reported race revealed differing ORs for GrimAge acceleration: White women (OR = 1.17; 95% CI: 1.03, 1.36), and Black women (OR = 1.08; 95% CI: 0.96, 1.23). However, our limited sample size failed to detect a statistically significant interaction for self-reported race (p-value >0.05) when examining GrimAge acceleration with BrCa risk., Conclusions: Our study demonstrated that epigenetic age acceleration is associated with BrCa risk, and the association suggests variation by self-reported race. Although our sample size is limited, these results highlight a potential biological mechanism for BrCa risk and identifies a novel research area of BrCa health disparities requiring further inquiry., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Estimation of admixture proportions has become one of the most commonly used computational tools in population genomics. However, there is remarkably little population genetic theory on statistical properties of these variables. We develop theoretical results that can accurately predict means and variances of admixture proportions within a population using models with recombination and genetic drift. Based on established theory on measures of multilocus disequilibrium, we show that there is a set of recurrence relations that can be used to derive expectations for higher moments of the admixture proportions distribution. We obtain closed form solutions for some special cases. Using these results, we develop a method for estimating admixture parameters from estimated admixture proportions obtained from programs such as Structure or Admixture. We apply this method to HapMap 3 data and find that the population history of African Americans, as expected, is not best explained by a single admixture event between people of European and African ancestry. The model of constant gene flow starting at 8 generations and ending at 2 generations before present gives the best fit., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD., Methods: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors., Results: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures., Discussion: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD., Highlights: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Individuals with diabetes who carry genetic variants that lower hemoglobin A1c (HbA1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared with those without these variants despite achieving similar HbA1c targets, potentially placing them at greater risk for diabetes-related complications. We sought to determine whether these genetic variants, aggregated in a polygenic score, and the large-effect African ancestry-specific missense variant in G6PD (rs1050828) that lower HbA1c were associated with higher retinopathy risk., Research Design and Methods: Using data from 29,828 type 2 diabetes cases of genetically inferred African American/African British and European ancestries, we calculated ancestry-specific nonglycemic HbA1c polygenic scores (ngA1cPS) composed of 122 variants associated with HbA1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS and the G6PD variant with retinopathy, adjusting for measured HbA1c and retinopathy risk factors., Results: Participants in the bottom quintile of the ngA1cPS showed between 20% and 50% higher retinopathy prevalence, compared with those above this quintile, despite similar levels of measured HbA1c. The adjusted meta-analytic odds ratio for the bottom quintile was 1.31 (95% CI 1.0, 1.73; P = 0.05) in African ancestry and 1.31 (95% CI 1.15, 1.50; P = 6.5 × 10-5) in European ancestry. Among individuals of African ancestry with HbA1c below 7%, retinopathy prevalence was higher in individuals below, compared with above, the 50th percentile of the ngA1cPS regardless of sex or G6PD carrier status., Conclusions: Genetic effects need to be considered to personalize HbA1c targets and improve outcomes of people with diabetes from diverse ancestries., (© 2024 by the American Diabetes Association.)

There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR., (© 2024. The Author(s).)

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx&#95;combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx&#95;combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Racial disparities in prostate cancer are likely the result of complex relationships between both socioeconomic and environmental factors captured by the neighborhood environment and genetic factors, including West African genetic ancestry. However, few studies have examined the combined role of neighborhood environment and genetic ancestry in developing lethal prostate cancer., Objective: To examine the interactions between West African genetic ancestry and neighborhood deprivation in modifying prostate cancer risk and mortality., Design, Setting, and Participants: This case-control study was conducted in the Greater Baltimore area. Participants included men of African and European descent (617 cases with prostate cancer, 852 controls without prostate cancer) enrolled between January 2005 and January 2016. Follow-up was performed through December 31, 2020, using the National Death Index. Analysis was conducted from August 2023 to January 2024., Exposure: Included exposures were West African genetic ancestry, derived from large-scale genotyping, and neighborhood deprivation, defined using 2000 census-tract-level Neighborhood Deprivation Index (NDI) score., Main Outcomes and Measures: Outcomes of interest were prostate cancer and all-cause mortality., Results: Among a total of 1469 participants (mean [SD] age, 64.96 [7.95] years), there were 736 self-identified Black and 733 White men, and the mean (range) proportion of West African genetic ancestry was 0.27 (0.04-0.84) among participants residing in areas with low levels of deprivation and 0.48 (0.07-0.83) among participants residing in areas with high levels of deprivation. Multivariable logistic regression analysis revealed a significant multiplicative interaction of West African genetic ancestry and neighborhood deprivation with the odds of a prostate cancer diagnosis (P for interaction = .02). Among individuals living in neighborhoods with high NDI scores, West African genetic ancestry was associated with increased odds of a prostate cancer diagnosis (age-adjusted odds ratio [OR], 1.98; 95% CI, 1.23-3.19). In contrast, West African genetic ancestry was associated with reduced odds of this diagnosis among individuals residing in areas with medium to low levels of deprivation (age-adjusted OR, 0.22; 95% CI, 0.11-0.44). There was no significant multiplicative interaction between West African genetic ancestry and neighborhood deprivation for all-cause mortality (P for interaction = .44). The positive association of neighborhood deprivation with prostate cancer was independent of West African genetic ancestry (age- and West African ancestry-adjusted OR, 1,70; 95% CI, 1.50-1.94)., Conclusions and Relevance: This case-control study of men with West African and European ancestry found that West African genetic ancestry was associated with increased odds of prostate cancer among males who resided in neighborhoods with high deprivation but lower odds in more affluent neighborhoods. Thus, neighborhood environments may play a critical role in defining how genetic ancestry modulates prostate cancer risk.

Background: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated., Methods: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up., Results: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups., Conclusions: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women., (© 2024. The Author(s).)

Background: Mitochondrial dysfunction manifests in neurodegenerative diseases and other age-associated disorders. In this study, we examined variation in inherited mitochondrial DNA (mtDNA) sequences in Black and White participants from 2 large aging studies to identify variants related to cognitive function., Methods: Participants included self-reported Black and White adults aged ≥70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N = 1 319) and Health Aging and Body Composition (Health ABC; N = 788) studies. Cognitive function was measured by the Digit-Symbol Substitution Test (DSST), and the Modified Mini-Mental State Examination (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined the joint effects of multiple variants across 16 functional mitochondrial regions with cognitive function using a sequence kernel association test. Based on these results, we prioritized meta-analysis of common variants in Black and White participants using mixed effects models. A Bonferroni-adjusted p value of <.05 was considered statistically significant., Results: Joint variation in subunits ND1, ND2, and ND5 of Complex I, 12S RNA, and hypervariable region (HVR) were significantly associated with DSST and 3MSE at baseline. In meta-analyses among Black participants, variant m.4216T>C, ND1 was associated with a faster decline in 3MSE, and variant m.462C>T in the HVR was associated with a slower decline in DSST. Variant m.5460G>C, ND2 was associated with slower and m.182C>T in the HVR was associated with faster decline in 3MSE in White participants., Conclusions: Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients., Objective: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women., Study Design: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses., Results: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38., Conclusion: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Nonalcoholic fatty liver disease (NAFLD) is less frequent in non-Hispanic persons (NHB), but there are knowledge gaps in our understanding of disease severity and outcomes of NAFLD in NHB. We compared liver histology and clinical outcomes of NAFLD in non-Hispanic Black persons (NHB) and non-Hispanic White persons (NHW)., Methods: We compared liver histology and outcomes of 109 NHB and 1,910 NHW adults with biopsy-proven NAFLD participating in the Nonalcoholic Steatohepatitis Clinical Research Network observational studies. The relationship between self-reported NHB race/ethnicity and advanced fibrosis was assessed through multivariable logistic regression after controlling for clinical covariates and PNPLA3 genotype., Results: NHB and NHW with NAFLD had similar NAFLD activity scores (NAS, 4.4 vs 4.3, P = 0.87) and proportions with definite metabolic dysfunction-associated steatohepatitis (59% vs 58%, P = 1.0), but NHB had significantly lower rates of advanced fibrosis (22% vs 34%, P = 0.01) or cirrhosis (4.6% vs 12.1%, P = 0.010). Compared with NHW, NHB had significantly lower frequency of advanced fibrosis (Odds Ratio: 0.48, 95% Confidence Interval: 27-0.86, P = 0.01). In a comparison between 24 NHB and 655 NHW with advanced fibrosis, the NAS (5.6 vs 4.9, P = 0.01) and lobular inflammation grade (2.2 vs 1.7, P < 0.002) were significantly higher among NHB with advanced fibrosis. One NHB and 23 NHW died during follow-up (0.30 vs 0.28 per 100 person-year follow-up). Seven and zero liver-related deaths occurred in NHW and NHB with NAFLD, respectively., Discussion: The risk of advanced fibrosis in NHB with NAFLD is significantly lower, after controlling for clinical risk factors and PNPLA3 genotype. Although their risk of advanced fibrosis was low, NHB with NAFLD and advanced fibrosis had higher NAS and lobular inflammation, indicating a difference in their relationship between necroinflammation and fibrosis., (Copyright © 2024 by The American College of Gastroenterology.)

Phenotypical innovations during evolution are caused by novel mutations, which are usually heterozygous at the beginning. The gene expressions on two alleles of these mutation sites are not necessarily identical, leading to flexible allele-specific regulation in cell systems. We retrieve the transcriptome data of normal and non-small cell lung cancer (NSCLC) tissues from 47 African Americans (AA) and 50 European Americans (EA). We analyze the differentially expressed genes (DEGs) in NSCLC as well as the tumor-specific mutations. Expression and mutation profiles show convergent evolution in AA and EA populations. The tumor-specific mutations are poorly overlapped, but many of them are located in the same genes, mainly oncogenes and tumor suppressor genes. The DEGs in tumors are majorly caused by the mutated alleles rather than normal alleles. The relative expressions of mutated alleles are highly correlated between AA and EA. The differential expression in NSCLC is predominantly mediated by the mutated alleles on heterozygous sites. This molecular mechanism underlying NSCLC oncogenesis is conserved across different human populations, exhibiting convergent evolution. We present this novel angle that differential expression analysis should be performed separately for different alleles. Our ideas should greatly benefit the cancer community., (© 2023. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)

Background: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive., Objective: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women., Study Design: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16)., Results: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women., Conclusion: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10 -8 ), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10 -9 ), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10 -8 ), PVRL2 (Score = 125.86, P = 1.64 × 10 -9 ), TOMM40 (Score = - 18.58, P = 4.61 × 10 -8 ), and APOE (Score = 75.12, P = 7.26 × 10 -26 ). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW., (© 2024. The Author(s).)

Significant racial disparities exist between Black and White patients with uterine serous carcinoma (USC). While the reasons for these disparities are unclear, several studies have demonstrated significantly different rates of driver mutations between racial groups, including TP53. However, limited research has investigated the transcriptional differences of tumors or the composition of the tumor microenvironment (TME) between these groups. Here, we report the single-nuclei RNA-sequencing profiles of primary USC tumors from diverse racial backgrounds. We find that there are significant differences between the tumors of Black and White patients. Tumors from Black patients exhibited higher expression of specific genes associated with aggressiveness, such as PAX8, and axon guidance and synaptic signaling pathways. We also demonstrated that T cell populations are reduced in the tumor tissue compared to matched benign, while anti-inflammatory macrophage populations are retained within the TME. Furthermore, we investigated the connection between PAX8 overexpression and immunosuppression in USC through regulation of several cytokines and chemokines. Notably, we show that PAX8 activity can influence macrophage gene expression and protein secretion. These studies provide a detailed understanding of the USC transcriptome and TME, and identify differences in tumor biology from patients of different racial backgrounds., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Gestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes., Methods: GAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays)., Results: GAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p < 0.05 for all)., Conclusions: GAmAge estimation is robust across different populations and racial/ethnic subgroups. GAmAge may be utilized as a proxy for GEAA and for assessing fetus development, indicated by inflammatory state and birth outcomes., (© 2024. The Author(s).)

Introduction: Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS., Materials and Methods: Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1)., Results: In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels., Conclusions: Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Background: High-grade serous carcinoma (HGSC) gene expression subtypes are associated with differential survival. We characterized HGSC gene expression in Black individuals and considered whether gene expression differences by self-identified race may contribute to poorer HGSC survival among Black versus White individuals., Methods: We included newly generated RNA sequencing data from Black and White individuals and array-based genotyping data from four existing studies of White and Japanese individuals. We used K-means clustering, a method with no predefined number of clusters or dataset-specific features, to assign subtypes. Cluster- and dataset-specific gene expression patterns were summarized by moderated t-scores. We compared cluster-specific gene expression patterns across datasets by calculating the correlation between the summarized vectors of moderated t-scores. After mapping to The Cancer Genome Atlas-derived HGSC subtypes, we used Cox proportional hazards models to estimate subtype-specific survival by dataset., Results: Cluster-specific gene expression was similar across gene expression platforms and racial groups. Comparing the Black population with the White and Japanese populations, the immunoreactive subtype was more common (39% vs. 23%-28%) and the differentiated subtype was less common (7% vs. 22%-31%). Patterns of subtype-specific survival were similar between the Black and White populations with RNA sequencing data; compared with mesenchymal cases, the risk of death was similar for proliferative and differentiated cases and suggestively lower for immunoreactive cases [Black population HR = 0.79 (0.55, 1.13); White population HR = 0.86 (0.62, 1.19)]., Conclusions: Although the prevalence of HGSC subtypes varied by race, subtype-specific survival was similar., Impact: HGSC subtypes can be consistently assigned across platforms and self-identified racial groups., (©2024 American Association for Cancer Research.)

Background: Although molecular biomarkers have significantly advanced precision oncology in glioblastoma, the prevalence of these biomarkers by race remains underexplored. This study aims to characterize the genomic alterations in glioblastoma across Asian, Black, and White patients, offering insights into racial disparities that may influence treatment outcomes and disease progression., Methods: Analyzing data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database V13.0, this study examined 2390 primary glioblastoma samples from unique patients. Genomic alterations in 566 cancer-related genes were assessed using targeted next-generation sequencing panels from 3 large cancer institutes. The patient cohort included 112 Asians, 67 Blacks, and 2211 Whites. Statistical significance of associations between genomic alterations and race was evaluated using the chi-squared test, with the Benjamini-Hochberg method applied to control for multiple testing adjustments., Results: Significant racial differences were observed in the frequency of genomic alterations. Asians exhibited a higher frequency of TP53 alterations (52.68%, P < 0.001), Blacks showed more frequent alterations in NRAS (7.46%, P < 0.001), MTOR (10.45%, P = 0.039), and TET2 (8.96%, P = 0.039), and Whites had a higher occurrence of PTEN alterations (48.67%, P = 0.045). Additionally, Black patients had an elevated rate of RET deletions (14.29%, P < 0.001)., Conclusions: This study identifies significant racial disparities in the alteration frequencies of 6 key glioblastoma genes: NRAS, TP53, MTOR, TET2, PTEN, and RET. These findings underscore the need for racial considerations in glioblastoma treatment strategies and highlight potential avenues for targeted therapeutic interventions. Further research is needed to explore the clinical implications of these genomic disparities., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Black men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC., Methods: We performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441)., Results: We identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR. The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes., Conclusions: These findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Blacks/African American (BAA) patients diagnosed with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes than White patients. However, the mechanisms underlying racial disparities in HNSCC have not been thoroughly characterized., Methods: Data on gene expression, copy number variants (CNVs), gene mutations, and methylation were obtained from 6 head and neck cancer datasets. Comparative bioinformatics analysis of the above genomic features was performed between BAAs and Whites. The expression pattern of GSTM1 was validated by immunohistochemistry using tumor tissue microarray (TMA). Effect of GSTM1 knockdown were assessed by cell proliferation, colony formation, and tumor development in an orthotopic mouse model. The changes in protein kinases were determined using the Proteome Profiler Human Phospho-Kinase Array Kit in HNSCC cells with or without GSTM1 knockdown., Results: We identified ancestry-related differential genomic profiles in HNSCC. Specifically, in BAA HNSCC, FAT1 mutations were associated with its gene expression, SALL3 gene expression correlated with its gene CNVs, and RTP4 gene expression showed an inverse correlation with its methylation. Notably, GSTM1 emerged as a prognostic risk factor for BAA HNSCC, with high gene CNVs and expression levels correlating with poor overall survival in BAA patients. Immunohistochemistry results from newly developed in-house TMA validated the expression pattern of GSTM1 between BAA HNSCC and White HNSCC. In an orthotopic mouse model, GSTM1 knockdown significantly inhibited malignant progression in tumors derived from BAAs. In contrast, loss of GSTM1 did not affect the development of HNSCC originating in Whites. Mechanistically, GSTM1 knockdown suppressed HSP27 phosphorylation and β-catenin in BAA HNSCC cells, but not in White HNSCC cells. This differential effect at least partially contributes to tumor development in BAA patients., Conclusion: This study identifies GSTM1 as a novel molecular determinant of survival in HNSCC patients of African descent. It also provides a molecular basis for future research focused on identifying molecular determinants and developing therapeutic interventions to improve outcomes for BAA patients with HNSCC., (© 2024. The Author(s).)

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings., Competing Interests: Declaration of interests N.S.A.-H. is currently employed by 23andMe, was previously employed by Regeneron Pharmaceuticals, received personal fees from Genentech, Allelica, and 23andMe, received research funding from Akcea, and serves as a scientific advisory board member for Allelica. E.E.K. received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass, Bio, Overtone, and Galateo Bio., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the 6 th leading cause of cancer-related mortality, with racial disparities amplifying the challenges in treatment. Although the relationship between hybrid epithelial/mesenchymal (E/M) states and tumor progression is of interest, no studies have characterized the clinical relevance of hybrid E/M states in head and neck cancer outcomes among self-reported racial cohorts., Methods: Given the overlap in gene expression between hybrid E/M malignant cells and cancer-associated fibroblasts, we utilized deconvolution of bulk RNA sequencing data from oral cavity and laryngeal squamous cell carcinoma tumors from The Cancer Genome Atlas. We utilized our previously collected single-cell profiles to generate inferred malignant profiles and then scored these for hybrid E/M. We then conducted a survival analysis on overall and disease-free survival among self-reported Black and White Americans., Findings: The hybrid E/M state was differentially associated with head and neck cancer survival by self-reported race and ethnicity, with a stronger association in non-Hispanic Black patients. Black patients with a high hybrid E/M score had a higher risk of death or recurrence (hazard ratio [HR]: 4.18 [95% confidence interval (CI): 2.06, 8.49]) than White patients with a high hybrid E/M score (HR: 1.58 [95% CI: 1.11, 2.26])., Conclusion: Our results suggest a complex interplay of social structure, racism, and genetic diversity. We implore researchers to consider the social and biological context contributing to disparities., Funding: A.L.M. received support from the National Institute of Minority Health and Health Disparities (K01MD013897 [principal investigator (PI), A.L.M.]). S.V.P. received support from the National Institute of Dental and Craniofacial Research (R01DE032865 [PI, S.V.P.] and R01DE032371 [PI, S.V.P.])., Competing Interests: Declaration of interests J.P.Z. is a founder and equity shareholder in Droplet Biosciences, an equity shareholder in Summit Biolabs, a consultant for Merck, and receives clinical trial funding from Merck. S.V.P., I.T., and A.S.P. are co-inventors on a patent related to partial EMT., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study investigates the genetic factors contributing to the disparity in prostate cancer incidence and progression among African American men (AAM) compared to European American men (EAM). The research focuses on employing Weighted Gene Co-expression Network Analysis (WGCNA) on public microarray data obtained from prostate cancer patients. The study employed WGCNA to identify clusters of genes with correlated expression patterns, which were then analyzed for their connection to population backgrounds. Additionally, pathway enrichment analysis was conducted to understand the significance of the identified gene modules in prostate cancer pathways. The Least Absolute Shrinkage and Selection Operator (LASSO) and Correlation-based Feature Selection (CFS) methods were utilized for selection of biomarker genes. The results revealed 353 differentially expressed genes (DEGs) between AAM and EAM. Six significant gene expression modules were identified through WGCNA, showing varying degrees of correlation with prostate cancer. LASSO and CFS methods pinpointed critical genes, as well as six common genes between both approaches, which are indicative of their vital role in the disease. The XGBoost classifier validated these findings, achieving satisfactory prediction accuracy. Genes such as APRT, CCL2, BEX2, MGC26963, and PLAU were identified as key genes significantly associated with cancer progression. In conclusion, the research underlines the importance of incorporating AAM and EAM population diversity in genomic studies, particularly in cancer research. In addition, the study highlights the effectiveness of integrating machine learning techniques with gene expression analysis as a robust methodology for identifying critical genes in cancer research., (© 2024. The Author(s).)

PARP is a nuclear enzyme with a major function in the DNA damage response. PARP inhibitors (PARPi) have been developed for treating tumors harboring homologous recombination repair defects that lead to a dependency on PARP. There are currently three PARPi approved for use in advanced prostate cancer, and several others are in clinical trials for this disease. Recent clinical trial results have reported differential efficacy based on the specific PARPi utilized as well as patient race. There is a racial disparity in prostate cancer, in which African American males are twice as likely to develop and die from the disease compared with European American males. Despite the disparity, there continues to be a lack of diversity in clinical trial cohorts for prostate cancer. In this review, PARP nuclear functions, inhibition, and clinical relevance are explored through the lens of racial differences. This review will touch on the biological variations that have been explored thus far between African American and European American males with prostate cancer to offer a rationale for investigating PARPi response in the context of race at both basic science and clinical development levels., (©2024 The Authors; Published by the American Association for Cancer Research.)

Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations., Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes., Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024., Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants' addresses. Self-reported race was determined using electronic medical records., Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included., Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (β = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, β = 0.008; SE, 0.003; P = .01; q value = .21)., Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.

Importance: Nutritive compounds play critical roles in DNA replication, maintenance, and repair, and also serve as antioxidant and anti-inflammatory agents. Sufficient dietary intakes support genomic stability and preserve health., Objective: To investigate the associations of dietary patterns, including intakes of essential nutrients and added sugar, and diet quality scores of established and new nutrient indices with epigenetic age in a diverse cohort of Black and White women at midlife., Design, Setting, and Participants: This cross-sectional study included analyses (2021-2023) of past women participants of the 1987-1997 National Heart, Lung, and Blood Institute Growth and Health Study (NGHS), which examined cardiovascular health in a community cohort of Black and White females aged between 9 and 19 years. Of these participants who were recruited between 2015 and 2019 from NGHS's California site, 342 females had valid completed diet and epigenetic assessments. The data were analyzed from October 2021 to November 2023., Exposure: Diet quality scores of established nutrient indices (Alternate Mediterranean Diet [aMED], Alternate Healthy Eating Index [AHEI]-2010); scores for a novel, a priori-developed Epigenetic Nutrient Index [ENI]; and mean added sugar intake amounts were derived from 3-day food records., Main Outcomes and Measures: GrimAge2, a second-generation epigenetic clock marker, was calculated from salivary DNA. Hypotheses were formulated after data collection. Healthier diet indicators were hypothesized to be associated with younger epigenetic age., Results: A total of 342 women composed the analytic sample (mean [SD] age, 39.2 [1.1] years; 171 [50.0%] Black and 171 [50.0%] White participants). In fully adjusted models, aMED (β, -0.41; 95% CI, -0.69 to -0.13), AHEI-2010 (β, -0.05; 95% CI, -0.08 to -0.01), and ENI (β, -0.17; 95% CI, -0.29 to -0.06) scores, and added sugar intake (β, 0.02; 95% CI, 0.01-0.04) were each significantly associated with GrimAge2 in expected directions. In combined analyses, the aforementioned results with GrimAge2 were preserved with the association estimates for aMED and added sugar intake retaining their statistical significance., Conclusions and Relevance: In this cross-sectional study, independent associations were observed for both healthy diet and added sugar intake with epigenetic age. To our knowledge, these are among the first findings to demonstrate associations between added sugar intake and epigenetic aging using second-generation epigenetic clocks and one of the first to extend analyses to a diverse population of Black and White women at midlife. Promoting diets aligned with chronic disease prevention recommendations and replete with antioxidant or anti-inflammatory and pro-epigenetic health nutrients while emphasizing low added sugar consumption may support slower cellular aging relative to chronological age, although longitudinal analyses are needed.

Importance: Variation in DNA methylation at specific loci estimates biological age, which is associated with morbidity, mortality, and social experiences. Aging estimates known as epigenetic clocks, including the Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), were trained on data predominately from individuals of European ancestry; however, limited research has explored DunedinPACE in underrepresented populations experiencing health disparities., Objective: To investigate associations of neighborhood and individual sociobehavioral factors with biological aging in a racially and ethnically diverse population., Design, Setting, and Participants: This cohort study, part of the Multiethnic Cohort study conducted from May 1993 to September 1996 to examine racial and ethnic disparities in chronic diseases, integrated biospecimen and self-reported data collected between April 2004 and November 2005 from healthy Hawaii residents aged 45 to 76 years. These participants self-identified as of Japanese American, Native Hawaiian, or White racial and ethnic background. Data were analyzed from January 2022 to May 2024., Main Outcomes and Measures: DNA methylation data were generated from monocytes enriched from cryopreserved lymphocytes and used to derive DunedinPACE scores from November 2017 to June 2021. Neighborhood social economic status (NSES) was estimated from 1990 US Census Bureau data to include factors such as educational level, occupation, and income. Individual-level factors analyzed included educational level, body mass index (BMI), physical activity (PA), and diet quality measured by the Healthy Eating Index (HEI). Linear regression analysis of DunedinPACE scores was used to examine their associations with NSES and sociobehavioral variables., Results: A total of 376 participants were included (113 [30.1%] Japanese American, 144 [38.3%] Native Hawaiian, and 119 [31.6%] White; 189 [50.3%] were female). Mean (SE) age was 57.81 (0.38) years. Overall, mean (SE) DunedinPACE scores were significantly higher among females than among males (1.28 [0.01] vs 1.25 [0.01]; P = .005); correlated negatively with NSES (R = -0.09; P = .08), HEI (R = -0.11; P = .03), and educational attainment (R = -0.15; P = .003) and positively with BMI (R = 0.31; P < .001); and varied by race and ethnicity. Native Hawaiian participants exhibited a higher mean (SE) DunedinPACE score (1.31 [0.01]) compared with Japanese American (1.25 [0.01]; P < .001) or White (1.22 [0.01]; P < .001) participants. Controlling for age, sex, HEI, BMI, and NSES, linear regression analyses revealed a negative association between educational level and DunedinPACE score among Japanese American (β, -0.005 [95% CI, -0.013 to 0.002]; P = .03) and Native Hawaiian (β, -0.003 [95% CI, -0.011 to 0.005]; P = .08) participants, yet this association was positive among White participants (β, 0.007; 95% CI, -0.001 to 0.015; P = .09). Moderate to vigorous PA was associated with lower DunedinPACE scores only among Native Hawaiian participants (β, -0.006; 95% CI, -0.011 to -0.001; P = .005), independent of NSES., Conclusions and Relevance: In this study of a racially and ethnically diverse sample of 376 adults, low NSES was associated with a higher rate of biological aging measured by DunedinPACE score, yet individual-level factors such as educational level and physical activity affected this association, which varied by race and ethnicity. These findings support sociobehavioral interventions in addressing health inequities.

Purpose: African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals., Methods: MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson's chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant., Results: Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM , BRCA1 , BRCA2 , PALB2 , and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1 , BRCA2 , and PALB2 were higher in AA/B compared with NHW individuals ( P < .001)., Conclusion: Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.

African American (AA) women are twice as likely to develop triple-negative breast cancer (TNBC) as women of European descent. Additionally, AA women with TNBC present a much more aggressive disease course than their European American (EA) counterparts. Thus, there is an unmet clinical need to identify race-specific biomarkers and improve survival outcomes in AA patients with TNBC. The minus-end directed microtubule motor protein kinesin family member C1 (KIFC1) promotes centrosome clustering and chromosomal instability and is often overexpressed in TNBC. Previous findings suggest that KIFC1 plays a role in cell proliferation and migration in TNBC cells from AAs and that the levels of nuclear KIFC1 (nKIFC1) are particularly high in AA patients with TNBC. The nuclear localization of KIFC1 in interphase may underlie its previously unrecognized race-specific association. In this study, we found that in TNBC cells derived from AAs, nKIFC1 interacted with the tumor suppressor myosin heavy chain 9 (MYH9) over EA cells. Treatment of AA TNBC cells with commercial inhibitors of KIFC1 and MYH9 disrupted the interaction between KIFC1 and MYH9. To characterize the racial differences in the KIFC1-MYH9-MYC axis in TNBC, we established homozygous KIFC1 knockout (KO) TNBC cell lines. KIFC1 KO significantly inhibited proliferation, migration, and invasion in AA TNBC cells but not in EA TNBC cells. RNA sequencing analysis showed significant downregulation of genes involved in cell migration, invasion, and metastasis upon KIFC1 KO in TNBC cell lines from AAs compared to those from EAs. These data indicate that mechanistically, the role of nKIFC1 in driving TNBC progression and metastasis is stronger in AA patients than in EA patients, and that KIFC1 may be a critical therapeutic target for AA patients with TNBC., (© 2024. The Author(s).)

Background: For patients with weak or discrepant RhD RBC phenotypes, RHD genotyping is employed to determine need for RhD-negative management. However, many RHD variants are type D-negative or D-positive. Serological recognition rates (RRs) of weak and partial RHD variants are poorly characterized., Study Design and Methods: Four US studies employing RHD genotyping for weak or discrepant RhD phenotypes provided data for race/ethnicity-specific serological recognition. Three studies used microplate, and 1 used gel and tube; 2 had anti-D data. We obtained White and Hispanic/Latino allele frequencies (AFs) of weak D types 1, 2, and 3 single-nucleotide variants (SNVs) from the Genome Aggregation Database (gnomAD, v4.0.0) and devised Hardy-Weinberg-based formulas to correct for gnomAD's overcount of hemizygous RHD SNVs as homozygous. We compiled common partial RHD AF from genotyped cohorts of US Black or sickle cell disease subjects. From variant AF, we calculated hemizygous-plus-homozygous genetic prevalences. Serological prevalence: genetic prevalence ratios yielded serological RRs., Results: Overall RRs of weak D types 1-3 were 17% (95% confidence interval 12%-24%) in Whites and 12% (5%-27%) in Hispanics/Latinos. For eight partial RHD variants in Blacks, overall RR was 11% (8%-14%). However, DAR RR was 80% (38%-156%). Compared to microplate, gel-tube recognition was higher for type 2 and DAU5 and lower for type 4.0. Anti-D was present in 6% of recognized partial RHD cases, but only in 0.7% of estimated total genetic cases., Discussion: Based on AF, >80% of patients with weak or partial RHD variants were unrecognized serologically. Although overall anti-D rates were low, better detection of partial RHD variants is desirable., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Alzheimer's disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain&#95;track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs., (© 2024. The Author(s).)

High-proportion spliced-in titin truncating variants (hiPSI TTNtvs) have been associated with an increased risk of atrial fibrillation, dilated cardiomyopathy (DCM) and heart failure in individuals of European ancestry 1 . However, similar data in individuals of African ancestry are lacking. Here we examined the association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure in individuals of African ancestry using data from the All of Us Research Program. Among 38,154 individuals of African ancestry, 169 (0.4%) individuals carried a hiPSI TTNtv. hiPSI TTNtv carriers were at a higher risk of developing atrial fibrillation (adjusted hazard ratio (HR adj ) 2.42, 95% confidence interval (CI) 1.52-3.85), DCM (HR adj 2.82, 95% CI 1.81-4.39) and heart failure (HR adj 2.07, 95% CI 1.43-3.00) compared with noncarriers. The association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure was similar in individuals of African ancestry and those of European ancestry. Therefore, genetic testing for hiPSI TTNtvs may permit early identification of carriers and support preventive measures to reduce the likelihood of heart failure development both in individuals of European ancestry and in individuals of African ancestry., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups., Methods: Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity., Results: We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women., Conclusions: The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.